It is well known that the D vitamins exhibit certain biological effects, such as stimulation of intestinal calcium absorption, stimulation of bone mineral resorption and the prevention of rickets. It is also well known that such biological activity is dependent upon these vitamins being altered in vivo, i.e. metabolized, hydroxylated derivatives. For example, current evidence indicates that 1α,25-dihydroxyvitamin D3 is the in vivo active form of vitamin D3 and is the compound responsible for the aforementioned biological effects.
The synthetic 1α-hydroxyvitamin D analogs, such as 1α-hydroxyvitamin D3, and 1α-hydroxyvitamin D2 also exhibit pronounced biological potency and such compounds as well as the natural metabolites show great promise as agents for the treatment of a variety of calcium metabolism and bone disorders, such as osteodystrophy, osteomalacia and osteoporosis.
Since 1α-hydroxylation is an essential element in imparting biological activity to the vitamin D compounds and their derivatives there has been increasing interest in methods for chemically accomplishing such hydroxylation. Except for one suggested method for the total synthesis of 1α-hydroxyvitamin D3, all syntheses of 1α-hydroxylated vitamin D compounds involved the preparation of a 1α-hydroxylated steroid, from which, after conversion to the corresponding 1α-hydroxy-5,7-diene sterol derivative, the desired vitamin D compound is obtained by well known photochemical methods.
Paricalcitol is a vitamin D2 derived sterol lacking the carbon-19 methylene group found in all natural vitamin D metabolites. A novel class of vitamin D-related compounds, namely the 1α-hydroxy-19-nor-vitamin D analogs, as well as a general method for their chemical synthesis are disclosed in U.S. Pat. Nos. 5,710,294 and 5,342,975. Furthermore, U.S. Pat. No. 6,359,012 provides the method for making 24(s)-hydroxyvitamin D2, which is the first stereospecific synthesis of 24(s)-hydroxyvitamin D2 by coupling of (s)-(+)-2,3-dimethyl-2-triethylsilyloxybutyraldehyde and a vitamin D phosphine oxide derivative to form a C-3 and C-24 diprotected trans-vitamin D2 which is then deprotected and irradiated to yield the 24(S)-hydroxyvitamin D2.